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Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways

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Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways biomolecules Article Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways Aayushi Srivastava 1,2,3,4 , Abhishek Kumar 1,5,6 , Sara Giangiobbe 1, Elena Bonora 7, Kari Hemminki 1, Asta Försti 1,2,3 and Obul Reddy Bandapalli 1,2,3,* 1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; [email protected] (A.S.); [email protected] (A.K.); [email protected] (S.G.); [email protected] (K.H.); [email protected] (A.F.) 2 Hopp Children’s Cancer Center (KiTZ), D-69120 Heidelberg, Germany 3 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), D-69120 Heidelberg, Germany 4 Medical Faculty, Heidelberg University, D-69120 Heidelberg, Germany 5 Institute of Bioinformatics, International Technology Park, Bangalore 560066, India 6 Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India 7 S.Orsola-Malphigi Hospital, Unit of Medical Genetics, 40138 Bologna, Italy; [email protected] * Correspondence: [email protected]; Tel.: +49-6221-42-1709 Received: 29 August 2019; Accepted: 10 October 2019; Published: 13 October 2019 Abstract: Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family. We performed whole genome sequencing on 23 affected and 3 unaffected family members from five NMTC-prone families and prioritized the identified variants using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). In total, 31 coding variants and 39 variants located in upstream, downstream, 50 or 30 untranslated regions passed FCVPPv2 filtering. Altogether, 210 genes affected by variants that passed the first three steps of the FCVPPv2 were analyzed using Ingenuity Pathway Analysis software. These genes were enriched in tumorigenic signaling pathways mediated by receptor tyrosine kinases and G-protein coupled receptors, implicating a central role of PI3K/AKT and MAPK/ERK signaling in familial NMTC. Our approach can facilitate the identification and functional validation of causal variants in each family as well as the screening and genetic counseling of other individuals at risk of developing NMTC. Keywords: papillary thyroid cancer; germline mutations; whole genome sequencing; predisposition markers; pathway analysis 1. Introduction Thyroid cancer is the most common endocrine malignancy with an age adjusted incidence of 0.5-20/100,000 persons per year [1]. Significant regional differences exist with Italy being among the countries with the highest incidence rates in the world [1]. An increasing incidence has been observed worldwide during the past decades, which can to a certain extent be related to changes in the availability of medical services and in standard clinical practice. On the other hand, regional Biomolecules 2019, 9, 605; doi:10.3390/biom9100605 www.mdpi.com/journal/biomolecules Biomolecules 2019, 9, 605 2 of 20 differences in incidence as well as changes over time may also be related to lifestyle, nutritional iodine, ionizing radiation and genetic factors [2]. For instance, the high incidence of thyroid cancer in Italy can be attributed to the disruptive and carcinogenic effect of volcanic environments on the endocrine system [3]. The familial relative risk of developing thyroid cancer is estimated to be increased 6.7-fold in a study based on the Swedish Family-Cancer Database, in which 3.4% of all thyroid cancer cases had a concordant family history [4]. Approximately 90–95% of all thyroid cancers are non-medullary thyroid cancers (NMTC) [5] and can be classified into four histological subtypes: papillary, follicular, Hürthle cell and anaplastic thyroid cancer, with papillary thyroid cancer (PTC) being the most common one. Familial NMTC (FNMTC) accounts for only a small percentage of all NMTCs and can be divided into non-syndromic and syndromic forms. In the first, it occurs as the primary feature and in the second, as a minor component of a familial cancer syndrome, such as familial adenomatous polyposis, Gardner’s syndrome, Cowden’s disease, Carney’s complex type 1, Werner’s syndrome, papillary renal neoplasia, and DICER1 syndrome [6]. Known syndromes explain only a small proportion of all FNMTCs. Unlike the case of familial medullary thyroid cancer, in which there is extensive evidence linking germline point mutations in the RET proto-oncogene to the development of thyroid cancer, the genetic causes for FNMTC remain largely unknown. Over the years, studies seeking genetic factors predisposing to NMTC have been performed using linkage analysis, candidate gene sequencing and recently also whole genome sequencing. These studies have suggested several genes as potential NMTC-predisposing genes, including, FOXE1, SRGAP1, TITF-1/NKX2.1, SRRM2, and HABP2 [7–11]. In addition, an imbalance of the telomere-telomerase complex has been demonstrated in the peripheral blood of familial PTC patients [12]. Nonetheless, NMTC is one of the most heritable cancers wherein first degree relatives of an affected individual have an 8-10-fold increased risk of developing the disease [13]. Therefore, there are many underlying germline mutations that are yet to be discovered. The identification of such predisposition genes could be of great value in the screening of individuals at risk of developing NMTCs as well as in the development of personalized adjuvant therapies based on the affected pathways. It has been observed that hereditary NMTC is characterized by early onset, a higher degree of aggressiveness and more frequent multifocal disease and recurrence compared with its sporadic counterpart [13]. Thus, medical centers recommend more aggressive treatment of affected family members, reinforcing the importance of identifying such cases. Here we report the germline genomic landscape of five families with NMTC aggregation consistent with an autosomal dominant pattern of inheritance. The aim of the current study was to use whole genome sequencing (WGS) data to discern pathways affected in the FNMTC families to facilitate the identification of possible disease-causing high/moderate-penetrance germline variants in each family. With our results, we hope to facilitate genetic counseling and targeted therapy in these families and improve screening of other individuals at risk of developing NMTC. 2. Materials and Methods 2.1. Ethical Approval Blood samples were collected from the participants with informed consent following ethical guidelines approved by “Comitato Etico Indipendente dell ‘Azienda Ospedaliero-Universitaria di Bologna, Policlinico S. Orsola-Malpighi (Bologna, Italy)” and “comité utiltative de protection des personnes dans la recherche biomédicale, Le centre de ute contre le cancer Léon-Bérard (Lyon, France)”. 2.2. NMTC Families Five families with NMTC aggregation consistent with an autosomal dominant pattern of inheritance were provided by the S. Orsola-Malpighi Hospital, Unit of Medical Genetics in Bologna, Italy. Samples from a total of 23 affected and 3 unaffected family members from the five families were submitted for WGS. Their respective pedigrees are shown in Figure1. In family 1, the mother (I-1) Biomolecules 2019, 9, 605 3 of 20 Biomolecules 2019, 9, x 3 of 23 was affected by insular carcinoma of the thyroid whereas three of her children and her grandchild diagnosedwere diagnosed with PTC with or PTCmicro-PTC or micro-PTC (II-2, II-3, (II-2, II-6, II-3,III-1) II-6, and III-1)one child and onewithchild benign with nodules benign (II-1). nodules Her unaffected(II-1). Her son una ffwasected deemed son was a reliable deemed control a reliable (II-4) control. WGS (II-4).(*) was WGS performed (*) was on performed five family on fivemembers. family Inmembers. family 2, Inthere family were 2, theresix cases were (III-1, six cases III-3, (III-1,III-4, III-3,IV-3, III-4,IV-4, IV-3,IV-5), IV-4, one IV-5),probable one case probable (IV-1) case and (IV-1) one controland one (IV-2) control out (IV-2)of which out six of whichunderwent six underwent WGS. Family WGS. 3 consisted Family 3 of consisted two related of two cases related (IV-4, cases IV-5)(IV-4, and oneIV-5) unrelated and one case unrelated (III-1) of case which (III-1) all three of which underwen all threet WGS. underwent Family 4 is WGS. characterized Family 4 by is bilateral characterized PTCs concurrentby bilateral with PTCs other concurrent subtypes withof NMTCs other subtypes(Hürthle ce ofll NMTCscancer, follicular (Hürthle canc celler). cancer, Four follicularfamily members cancer). wereFour diagnosed family members with thyroid were diagnosed cancer of withwhich thyroid all underwent cancer of WGS which (II-2, all III-1, underwent III-2, III-3). WGS WGS (II-2, was III-1, performedIII-2, III-3). on WGS eight was family performed members on eight of family family 5. members Five members of family were 5. Fiveaffected members by PTC, were Hürthle affected cell by cancer,PTC, Hürthle micro-PTC cell or cancer, a combination micro-PTC of ortwo a combinationof the subtypes of (II-2, two ofII-3, the II- subtypes5, II-8, II-9). (II-2, Four II-3, members II-5, II-8, were II-9). possibleFour members carriers were either possible affected carriers by benign either nodules affected or bydeceased benign (I-1, nodules II-4, II-6) or deceased and two (I-1, were II-4, unaffected II-6) and (II-1,two wereII-7). una ffected (II-1, II-7). FigureFigure 1. Pedigrees 1. Pedigrees of the of five the non-medullary five non-medullary thyroid thyroid canc cancerer (NMTC)-prone (NMTC)-prone families families analyzed analyzed in in this this study.
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